Compositions containing coenzyme q-10 and dihydrolipoic acid

ABSTRACT

The invention describes compositions, including soft gelatin capsules, that include dihydrolipoic acid and the reduced form of coenzyme Q n  wherein the dihydrolipoic acid acts as a reducing agent for the coenzyme Q n  and also, optionally, as a solvent.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.11/843,935, filed Aug. 23, 2007, which claims priority to Austrianpatent application A1422/2006, filed Aug. 25, 2006 and U.S. Provisionalapplication 60/886,395, filed Jan. 24, 2007, entitled “CompositionsContaining Coenzyme Q-10 and Dihydrolipoic Acid”, the contents of whichare incorporated herein in their entirety.

FIELD OF THE INVENTION

The invention relates generally unique combinations of a reduced form ofcoenzyme Q-10 (CoQ10). CoQ10 is reduced to ubiquinol in the presence ofdihydrolipoic acid (DHLA), where DHLA serves as not only the reducingagent but also as a carrier.

BACKGROUND OF THE INVENTION

CoQ-10 (coenzyme Q10) is a fat-soluble quinone, a benzoquinone that isstructurally similar to vitamin K and commonly known as ubiquinone.CoQ-10 is found in most living organisms, and is essential for theproduction of cellular energy. CoQ-10 (2,3 dimethyl-5methyl-6-decaprenyl benzoquinone) is an endogenous antioxidant found insmall amounts in meats and seafood. Although CoQ-10 is found in allhuman cells, the highest concentrations of CoQ-10 occur in the heart,liver, kidneys, and pancreas. It is found naturally in the organs ofmany mammalian species.

CoQ-10 is an important nutrient because it lies within the membrane of acell organelle called the mitochondria. Mitochondria are known as the“power house” of the cell because of their ability to produce cellularenergy, or ATP, by shuttling protons derived from nutrient breakdownthrough the process of aerobic (oxygen) metabolism. CoQ-10 also has asecondary role as an antioxidant. CoQ-10, due to the involvement in ATPsynthesis, affects the function of almost all cells in the body, makingit essential for the health of all human tissues and organs. CoQ-10particularly effects the cells that are the most metabolically active:heart, immune system, gingiva, and gastric mucosa

CoQ-10 is sparingly soluble in most hydrophilic solvents such as water.Therefore, CoQ-10 is often administered in a powdered form, as in atablet or as a suspension. However, delivery of CoQ-10 by these methodslimits the bioavailability of the material to the individual.

Several clinical trials have shown CoQ-10 to be effective in supportingblood pressure and cholesterol levels. Furthermore, CoQ-10 has also beenshown to improve cardiovascular health. CoQ-10 has been implicated asbeing an essential component in thwarting various diseases such ascertain types of cancers. These facts lead many to believe that CoQ-10supplementation is vital to an individual's well being.

Reduced benzoquinones are known to be effective reductants for oxygen orlipid radicals. Some studies have shown that reduced CoQ-10 (ubiquinol)is an effective antioxidant. In fact, reduced CoQ-10 now appears tofunction as part of a complex chain of antioxidant activity. Apparently,reduced CoQ-10 plays a role in the reduction of radicals ofalpha-tocopherol and ascorbate formed when these antioxidants areoxidized by oxygen or carboxyl radicals present in physiologicalsystems. There are no known enzymes for direct reduction of a tocopherylradical or an external ascorbate radical, but there are enzymes in allmembranes that can reduce CoQ-10 and thus reduced CoQ-10 cansubsequently reduce the tocopheryl or ascorbate radicals to providetocopherol or ascorbate. Without the support of enzymes to reduceCoQ-10, the reduced coQ-10 would not be a very effective antioxidant asthe semiquinone formed by interaction with lipid or oxygen radicals isreadily autooxidized with formation of a superoxide radical.

Therefore, a need exists for methods and compositions that providereduced CoQ-10 in a form that can be assimilated and retains antioxidantactivity.

BRIEF SUMMARY OF THE INVENTION

The present invention surprisingly provides solutions of coenzyme Q-10(CoQ-10) and reduced CoQ-10 with dihydrolipoic acid (DHLA).Interestingly, when at least a molar amount of DHLA is combined with amolar equivalent of CoQ-10, the oxidized form of CoQ-10 is reduced tothe reduced form of CoQ-10. Generally, greater than 90% of the oxidizedform of CoQ-10 is converted to the reduced form of CoQ-10 and inparticular greater than 95% conversion occurs, to a point whereessentially no oxidized CoQ-10 remains. Excess DHLA serves then as asolvent carrier and helps to stabilize the reduced CoQ-10, making shelfstable for extended periods of time.

In one aspect, the present invention provides a reduced coenzyme Q-10(CoQ-10) composition that includes a sufficient amount of dihydrolipoicacid (DHLA) to reduce CoQ-10 to a reduced form of CoQ-10 in greater than95% by weight. In certain embodiments, the composition does not includean ethanolic solution containing 8% water.

In another aspect, the present invention provides reduced coenzyme Q-10(CoQ-10) compositions that consist essentially of a sufficient amount ofdihydrolipoic acid (DHLA) to reduce CoQ-10 to a reduced form of CoQ-10in greater than 95% by weight.

In still another aspect, the present invention provides a soft gelatincapsule that encapsulates a reduced coenzyme Q-10 (CoQ-10) composition.The reduced CoQ-10 composition includes a sufficient amount ofdihydrolipoic acid (DHLA) to reduce CoQ-10 to a reduced form of CoQ-10in greater than 95% by weight.

In yet another aspect, the present invention provides a soft gelatincapsule that encapsulates a reduced coenzyme Q-10 (CoQ-10) compositionthat, consists essentially of: a sufficient amount of dihydrolipoic acid(DHLA) to reduce CoQ-10 to a reduced form of CoQ-10 in greater than 95%by weight.

The compositions and soft gelatin capsules can further include variouscarriers and additives, such as suitable antioxidants and/or vitamins.

The present invention also provides a method to prepare solutions ofreduced CoQ-10.

The present invention further provides methods to treat variousconditions associated with decreased levels of CoQ-10, such asmitochondrial related diseases and disorders, Parkinson's disease,Prater-Willey syndrome, migraine headaches or headaches by administeringto the individual in need thereof, an effective amount of any of thecompositions disclosed herein.

In still another aspect, the present invention also provides packagedneutraceuticals that are disclosed herein.

While multiple embodiments are disclosed, still other embodiments of thepresent invention will become apparent to those skilled in the art fromthe following detailed description. As will be apparent, the inventionis capable of modifications in various obvious aspects, all withoutdeparting from the spirit and scope of the present invention.Accordingly, the detailed descriptions are to be regarded asillustrative in nature and not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 exhibits the solubility of CoQ-10 at various temperatures inDHLA.

FIG. 2 is a UV spectrograph of the reaction between CoQ-10 and excessDHLA after 1 hour.

FIG. 3 is a UV spectrograph of the reaction between CoQ-10 and excessDHLA after 6 hours.

FIG. 4 is a graphical representation of the reduction of CoQ-10 withexcess DHLA over a 30-hour time period.

DETAILED DESCRIPTION

The present invention surprisingly provides solutions of coenzyme Q-10(CoQ-10) and reduced CoQ-10 with dihydrolipoic acid (DHLA).Interestingly, when at least a molar amount of DHLA is combined with amolar equivalent of CoQ-10, the oxidized form of CoQ-10 is reduced tothe reduced form of CoQ-10.

Generally, greater than 90% of the oxidized form of CoQ-10 is convertedto the reduced form of CoQ-10 and in particular greater than 95%, moreparticularly, 96%, still more particularly, 97%, more particularly 98%,still more particularly, 99% conversion occurs, to a point whereessentially no oxidized CoQ-10 remains. Excess DHLA serves then as asolvent carrier and helps to stabilize the reduced CoQ-10, making shelfstable for extended periods of time.

In one aspect, the present invention provides a reduced coenzyme Q-10(CoQ-10) composition that includes a sufficient amount of dihydrolipoicacid (DHLA) to reduce CoQ-10 to a reduced form of CoQ-10 in greater than95% by weight. In certain embodiments, the composition does not includean ethanolic solution containing 8% water.

In the specification and in the claims, the terms “including” and“comprising” are open-ended terms and should be interpreted to mean“including, but not limited to . . . ” These terms encompass the morerestrictive terms “consisting essentially of” and “consisting of”

Dihydrolipoic acid (DHLA) is a constituent of cellular metabolism. DHLAhas two thiol residues that make is susceptible to radical species, thusprovides antioxidant functionality to the biomolecule. Oxidationreduction (redox reactions) involves the transfer of an electron from adonor to an acceptor. When the donor loses an electron, it istransformed from its reduced form to its oxidized form. When an acceptorgains an electron, it changes from its oxidized form to its reducedform. Together, the oxidized and reduced forms of a redox component,such as lipoic acid and DHLA or CoQ-10 (ubiquinone) and reduced CoQ-10(ubiquinol) are called “redox couples.”

Dihydrolipoic acid is the reduced (has electrons added) form of lipoicacid (thioctic acid). When DHLA is oxidized (has electrons removed)lipoic acid is produced. It should be understood that DHLA can be eitherthe R or S enantiomer or it can be racemic. Likewise, lipoic acid canalso be enantiomerically pure or racemic.

Likewise, ubiquinol is the reduced (has electrons added) form ofubiquinone (CoQ-10). When ubiquinol is oxidized (has electrons removed),ubiquinone is produced.

Surprisingly, it has been found by the present invention that at pHranges of below 7, the present invention did not provide any indicationof a radical formation as noted by UV spectrometry. Not to be limited bytheory, it is believed that a “2 electron transfer” reaction takes placeunder these conditions. This seems also logical for, as at the pH of thereaction DHLA is not susceptible to radical formation, which would be aprerequisite for a radical reaction.

This results are surprising in that at pH values of 7 or greater,typically lipoic acid donates an electron to DHLA, and the DHLA reactswith a free radical and is then oxidized back into lipoic acid, and thelipoic acid is then reduced using cellular reducing equivalents (NADH orNADPH) back into DHLA thus continuing the redox cycle. As the two formsswap electrons, they rapidly convert. Many of the properties of lipoicacid depend on this ability to rapidly swap electrons. In combinationwith this redox pair, DHLA can donate an electron to other oxidizedspecies, such as CoQ-10, thus reducing the CoQ-10 to ubiquinol andoxidizing the DHLA to lipoic acid.

The term “coenzyme Q” or “ubiquinone” (CoQ-10) is used throughout thepresent specification to describe a group of lipid soluble benzoquinonesinvolved in electron transport in mitochondrial preparations, i.e., inthe oxidation of succinate or reduced nicotine adenine dinucleotide(NADH) via the cytochrome system. The compounds can be described as:coenzyme Q_(n) where n is 1-12 or ubiquinone (x) in which x designatesthe total number of carbon atoms in the side chain and can be anymultiple of 5. Differences in properties are due to the difference inthe chain length. In particular, ubiquinone for use in the presentinvention is the reduced form of coenzyme Q10, known as ubiquinol.Therefore, the term CoQ-10 includes all variations where n is from 1 to12. Likewise, reduced CoQ-10 also includes all variation where n is from1 to 12.

The term “ubiquinol” is used throughout the specification to describethe reduced form of coenzyme Q_(n) that is used as the active agent incompositions according to the present invention. In ubiquinol, thequinone ring of coenzyme Q_(n) is reduced such that the structure of thecompound appears as set forth below. In one aspect, ubiquinol, n ispreferably 10 and is derived from coenzyme Q₁₀. The amount of ubiquinolwhich is included in compositions according to the present inventionranges from about 0.1% to about 50% by weight of the final compositionwhich is encapsulated in a soft gelatin capsule, more preferably about0.5% to about 10% by weight, even more preferably about 1% to about 5%by weight. The amount of ubiquinol which is included in compositions tobe encapsulated ranges from about 0.1 to about 10.0 times, morepreferably about 1 to about 3 times the amount (in weight percent) ofthe lipid soluble reducing agent which is included in compositionsaccording to the present invention.

It should be understood, that throughout this specification, referenceto CoQ-10 and reduced CoQ-10 refers to all possible derivatives where nis as detailed above.

While not being limited by way of theory, it is believed that effectiveconcentrations of DHLA convert substantially all ubiquinone toubiquinol. In other embodiments, effective concentrations of DHLA alsohelp prevent ubiquinol from being oxidized to ubiquinone, oralternatively reduce any ubiquinone, which has been oxidized fromubiquinol during storage of the compositions according to the presentinvention.

The concentration of coenzyme Q10 in DHLA can range from about 1% toabout 33% (w/w), in particular, from about 3% to about 22%, mostparticularly from about 8% to about 15% (w/w). At higher concentrations,especially at 25% or more, there is a tendency of CoQ10 to crystallize.However, it has been found possible to produce solutions of CoQ10 inDHLA with a weight ratio of, for example, about 33% CoQ10 to about 67%DHLA or even 2 weight parts of CoQ10 to 1 weight part of DHLA, althoughthe reaction time to produce such solutions may be in the range ofseveral weeks.

Solutions containing a weight ratio of CoQ10 to DHLA of 2:1 or more tendto crystallize and to be present in solid form at room temperature.

The compositions according to the present invention can be present inliquid form. Otherwise, the composition can, at room temperature, bepresent as a gel or as a solid, dependent on the CoQ10-concentration,but may become liquid at body temperature (37° C.). If the concentrationof CoQ10 in a solution in DHLA is below 22%, a solid mixture will becomea clear solution within 6 minutes at a temperature of 37° C.

In one aspect, the dissolution step is carried out at a pH-value ofbelow 5. In one embodiment, the reaction medium generally does notinclude any solvent other than DHLA and no agent, which would adjust thepH to a value of 5 or higher.

The products according to the present invention are especially usefuldue to the fact that they are able to provide effective doses of bothreduced CoQ10 and DHLA/Lipoic Acid in one single product. TypicallyCoQ10 is dosed between about 10 to 30 mg and Lipoic Acid is dosedbetween 50 to 200 mg. Hence, e.g., 100 to 150 mg of a solution accordingto the present invention may deliver both CoQ10 and DHLA/Lipoic Acid atan effective concentration.

Suitable carriers include but are not limited to, for example, fattyacids, esters and salts thereof, that can be derived from any source,including, without limitation, natural or synthetic oils, fats, waxes orcombinations thereof. Moreover, the fatty acids can be derived, withoutlimitation, from non-hydrogenated oils, partially hydrogenated oils,fully hydrogenated oils or combinations thereof. Non-limiting exemplarysources of fatty acids (their esters and salts) include seed oil, fishor marine oil, canola oil, vegetable oil, safflower oil, sunflower oil,nasturtium seed oil; mustard seed oil, olive oil, sesame oil, soybeanoil, corn oil, peanut oil, cottonseed oil, rice bran oil, babassu nutoil, palm oil, low erucic rapeseed oil, palm kernel oil, lupine oil,coconut oil, flaxseed oil, evening primrose oil, jojoba, tallow, beeftallow, butter, chicken fat, lard, dairy butterfat, shea butter orcombinations thereof.

Specific non-limiting exemplary fish or marine oil sources includeshellfish oil, tuna oil, mackerel oil, salmon oil, menhaden, anchovy,herring, trout, sardines or combinations thereof. In particular, thesource of the fatty acids is fish or marine oil (DHA or EPA), soybeanoil or flaxseed oil. Alternatively or in combination with one of theabove identified carriers, beeswax can be used as a suitable carrier, aswell as suspending agents such as silica (silicon dioxide).

Specific non-limiting exemplary fish or marine oil sources includeshellfish oil, tuna oil, mackerel oil, salmon oil, menhaden, anchovy,herring, trout, sardines or combinations thereof. In particular, thesource of the fatty acids is fish or marine oil (DHA or EPA), soybeanoil or flaxseed oil. Alternatively or in combination with one of theabove identified carriers, beeswax can be used as a suitable carrier, aswell as suspending agents such as silica (silicon dioxide).

Additionally, limonene singly, and/or with other cyclic monoterpenecontaining essential oil(s), such as orange oil (which may contain 95%or more d-limonene) can be included with one or more carriers.Non-limiting examples of d-limonene containing oils include Lavindin,Peppermint, Ginger, Camphor, Geranium, Orange, Lemon, Lavender, TeaTree, and Rosemary.

The formulations of the invention are considered dietary supplementsuseful to the increase the amounts of reduced CoQ-10 and/or additionalantioxidants in individuals in need thereof.

The formulations of the invention can also be used in cosmetic products.

Alternatively, the formulations of the invention are also considered tobe nutraceuticals. The term “nutraceutical” is recognized in the art andis intended to describe specific chemical compounds found in foods thatmay prevent disease. Reduced CoQ-10 and antioxidants are such compounds.

The formulations of the invention can further include variousingredients to help stabilize, or help promote the bioavailability ofthe CoQ-10 and/or amino acid(s), or serve as additional nutrients to anindividual's diet. Suitable additives can include vitamins andbiologically-acceptable minerals. Non-limiting examples of vitaminsinclude vitamin A, B vitamins, vitamin C, vitamin D, vitamin E, vitaminK and folic acid. Non-limiting examples of minerals include iron,calcium, magnesium, potassium, copper, chromium, zinc, molybdenum,iodine, boron, selenium, manganese, derivatives thereof or combinationsthereof. These vitamins and minerals may be from any source orcombination of sources, without limitation. Non-limiting exemplary Bvitamins include, without limitation, thiamine, niacinamide, pyridoxine,riboflavin, cyanocobalamin, biotin, pantothenic acid or combinationsthereof.

Vitamin(s), if present, are present in the composition of the inventionin an amount ranging from about 5 mg to about 500 mg. More particularly,the vitamin(s) is present in an amount ranging from about 10 mg to about400 mg. Even more specifically, the vitamin(s) is present from about 250mg to about 400 mg. Most specifically, the vitamin(s) is present in anamount ranging from about 10 mg to about 50 mg. For example, B vitaminsare in usually incorporated in the range of about 1 milligram to about10 milligrams, i.e., from about 3 micrograms to about 50 micrograms ofB12. Folic acid, for example, is generally incorporated in a range ofabout 50 to about 400 micrograms, biotin is generally incorporated in arange of about 25 to about 700 micrograms and cyanocobalamin isincorporated in a range of about 3 micrograms to about 50 micrograms.

Mineral(s), if present, are present in the composition of the inventionin an amount ranging from about 25 mg to about 1000 mg. Moreparticularly, the mineral(s) are present in the composition ranging fromabout 25 mg to about 500 mg. Even more particularly, the mineral(s) arepresent in the composition in an amount ranging from about 100 mg toabout 600 mg.

Various additives can be incorporated into the present compositions.Optional additives of the present composition include, withoutlimitation, phospholipids, L-carnitine, starches, sugars, fats,antioxidants, amino acids, proteins, flavorings, coloring agents,hydrolyzed starch(es) and derivatives thereof or combinations thereof.

As used herein, the term “phospholipid” is recognized in the art, andrefers to phosphatidyl glycerol, phosphatidyl inositol, phosphatidylserine, phosphatidyl choline, phosphatidyl ethanolamine, as well asphosphatidic acids, ceramides, cerebrosides, sphingomyelins andcardiolipins.

As used herein, the term “antioxidant” is recognized in the art andrefers to synthetic or natural substances that prevent or delay theoxidative deterioration of a compound. Exemplary antioxidants includetocopherols, flavonoids, catechins, superoxide dismutase, lecithin,gamma oryzanol; vitamins, such as vitamins A, C (ascorbic acid) and Eand beta-carotene; natural components such as camosol, carnosic acid androsmanol found in rosemary and hawthorn extract, proanthocyanidins suchas those found in grapeseed or pine bark extract, and green tea extract.

The term “flavonoid” as used herein is recognized in the art and isintended to include those plant pigments found in many foods that arethought to help protect the body from cancer. These include, forexample, epi-gallo catechin gallate (EGCG), epi-gallo catechin (EGC) andepi-catechin (EC).

Any dosage form, and combinations thereof, are contemplated by thepresent invention. Examples of such dosage forms include, withoutlimitation, chewable tablets, elixirs, liquids, solutions, suspensions,emulsions, capsules, soft gelatin capsules, hard gelatin capsules,caplets, lozenges, chewable lozenges, suppositories, creams, topicals,ingestibles, injectables, infusions, health bars, confections, animalfeeds, cereals, cereal coatings, and combinations thereof. Thepreparation of the above dosage forms are well known to persons ofordinary skill in the art.

For example, health bars can be prepared, without limitation, by mixingthe formulation plus excipients (e.g., binders, fillers, flavors,colors, etc.) to a plastic mass consistency. The mass is then eitherextended or molded to form “candy bar” shapes that are then dried orallowed to solidify to form the final product.

Soft gel or soft gelatin capsules can be prepared, for example, withoutlimitation, by dispersing the formulation in an appropriate vehicle(e.g. rice bran oil, DHLA and/or beeswax) to form a high viscositymixture. This mixture is then encapsulated with a gelatin based filmusing technology and machinery known to those in the soft gel industry.The industrial units so formed are then dried to constant weight.Typically, the weight of the capsule is between about 100 to about 2500milligrams and in particular weigh between about 1500 and about 1900milligrams, and more specifically can weigh between about 1500 and about2000 milligrams.

For example, when preparing soft gelatin shells, the shell can includebetween about 20 to 70 percent gelatin, generally a plasticizer andabout 5 to about 60% by weight sorbitol. The filling of the soft gelatincapsule is liquid (principally limonene, in combination with rice branoil and/or beeswax if desired) and can include, apart form theantioxidant actives, a hydrophilic matrix. The hydrophilic matrix, ifpresent, is a polyethylene glycol having an average molecular weight offrom about 200 to 1000. Further ingredients are optionally thickeningagents. In one embodiment, the hydrophilic matrix includes polyethyleneglycol having an average molecular weight of from about 200 to 1000, 5to 15% glycerol, and 5 to 15% by weight of water. The polyethyleneglycol can also be mixed with propylene glycol and/or propylenecarbonate.

In another embodiment, the soft gel capsule is prepared from gelatin,glycerine, water and various additives. Typically, the percentage (byweight) of the gelatin is between about 30 and about 50 weight percent,in particular between about 35 and about weight percent and morespecifically about 42 weight percent. The formulation includes betweenabout 15 and about 25 weight percent glycerine, more particularlybetween about 17 and about 23 weight percent and more specifically about20 weight percent glycerine.

The remaining portion of the capsule is typically water. The amountvaries from between about 25 weigh percent and about 40 weight percent,more particularly between about 30 and about 35 weight percent, and morespecifically about 35 weight percent. The remainder of the capsule canvary, generally, between about 2 and about 10 weight percent composed ofa flavoring agent(s), sugar, coloring agent(s), etc. or combinationthereof. After the capsule is processed, the water content of the finalcapsule is often between about 5 and about 10 weight percent, moreparticularly 7 and about 12 weight percent, and more specificallybetween about 9 and about 10 weight percent.

As for the manufacturing, it is contemplated that standard soft shellgelatin capsule manufacturing techniques can be used to prepare thesoft-shell product. Examples of useful manufacturing techniques are theplate process, the rotary die process pioneered by R. P. Scherer, theprocess using the Norton capsule machine, and the Accogel machine andprocess developed by Lederle. Each of these processes are maturetechnologies and are all widely available to any one wishing to preparesoft gelatin capsules.

Typically, when a soft gel capsule is prepared, the total weight isbetween about 250 milligrams and about 2.5 gram in weight, e.g., 400-750milligrams. Therefore, the total weight of additives, such as vitaminsand antioxidants, is between about 80 milligrams and about 2000milligrams, alternatively, between about 100 milligrams and about 1500milligrams, and in particular between about 120 milligrams and about1200 milligrams. In particular, the soft gel capsule typically weighsbetween about 1000 milligrams and 1300 milligrams, wherein thepercentage fill is about 50% of the entire weight of the capsule, i.e.,from about 500 to about 650 milligrams fill weight. The fill weightincludes the active ingredient(s), solubilizing agents, etc.

Preparation of the soft gel capsules was accomplished by methods wellknown in the art including, but not limited to those describedthroughout the specification and in U.S. Pat. Nos. 6,616,942, 6,623,734and pending U.S. Ser. Nos. 10/035,753 and 09/825,920, the contents ofwhich are incorporated herein by reference in their entirety.

For example, a soft gel capsule can be prepared by mixing a DHLAsolution of reduced CoQ-10 to provide a syrupy mixture. The mixture isthen encapsulated within a gelatin capsule as described above.

Tablets, capsules, powders and/or solutions can include one or more ofexcipients, disintegrants, lubricants, binders, colorants, aggregationinhibitors, absorption enhancers, solubilizing agents, stabilizer andthe like.

Excipients include, for example, white sugar, lactose, glucose, cornstarch, mannitol, crystalline cellulose, calcium phosphate, calciumsulfate and the like.

Disintegrants include, for example, starch, agar, calcium citrate,calcium carbonate, sodium hydrogen carbonate, dextrin, crystallinecellulose, carboxymethylcellulose, tragacanth and the like.

Lubricants include, for example, talc, magnesium stearate, polyethyleneglycol, silica, hardened vegetable oils and the like.

Binders include, for example, ethylcellulose, methylcellulose,hydroxypropylmethylcellulose, tragacanth, shellac, gelatin, gum arabic,polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid,polymethacrylic acid, sorbitol and the like.

The present invention also provides packaged formulations of reducedCoQ-10 and/or CoQ-10 and DHLA and instructions for use of the tablet,capsule, elixir, etc. Typically, the packaged formulation, in whateverform, is administered to an individual in need thereof that requires anincrease in the amount of reduced CoQ-10 in the individual's diet.Typically, the dosage requirement is between about 1 to about 4 dosagesa day.

CoQ-10 has been implicated in various biochemical pathways and issuitable for the treatment of cardiovascular conditions, such as thoseassociated with, for example, statin drugs that effect the body'sability to product CoQ-10 naturally. CoQ-10 has also been implicated invarious periodontal diseases. Furthermore, CoQ-10 has been implicated inmitochondrial related diseases and disorders, such as the inability toproduct acetyl coenzyme A, neurological disorders, for example, such asParkinson's disease and, Prater-Willey syndrome, migraine headaches andheadaches.

The following paragraphs enumerated consequently from 1 through 63provide for various aspects of the present invention. In one embodiment,in a first paragraph (1), the present invention provides a reducedcoenzyme Q-10 (CoQ-10) composition, comprising:

a sufficient amount of dihydrolipoic acid (DHLA) to reduce CoQ-10 to areduced form of CoQ-10 in greater than 95% by weight, provided that thecomposition does not include an ethanolic solution containing 8% water.

2. The composition of the first paragraph, further comprising a carrier.

3. The composition of the second paragraph, wherein the carrier is DHLA.

4. The composition of the second paragraph, wherein the carrier is avegetable oil, a fish oil or a combination thereof.

5. The composition of any of paragraphs 1 through 4, further comprisinga an antioxidant or an antioxidant enzyme.

6. The composition of paragraph 5, wherein the antioxidant is vitamin E,a vitamin E derivative, vitamin C, a vitamin C derivative, probucol,lycopene, vitamin A, a carotenoid, vitamin B, vitamin B1, a vitamin Bderivative, a flavonoid, a polyphenol, glutathione, pyrroloquinolinequinone, Pycnogenol, Flavangenol, selenium, a lipoic acid, a lipoic acidderivative, a carnitine (e.g., L-carnitine) or mixtures thereof.

7. The composition of paragraph 5, wherein the antioxidant enzyme issuperoxide dismutase, glutathione peroxidase, glutathione-S-transferase,glutathione reductase, catalase and ascorbic acid peroxidase or mixturesthereof.

8. The composition of any of paragraphs 1 through 7, wherein the pHrange of the composition is between about a pH of 6 and a pH of 3.

9. The composition of paragraph 8, wherein the pH range is between about5.5 and about 3.5.

10. The composition of paragraph 9, wherein the pH range is betweenabout 4 and about 3.5.

11. The composition of paragraph 10, wherein the pH range is betweenabout 3.9 to about 3.8.

12. The composition of any of paragraphs 1 through 11, wherein thereduced form of CoQ-10 is present in an amount of about 98.5% by weightor greater.

13. The composition of any of paragraphs 1 through 11, whereinessentially all of the CoQ-10 is present in the reduced form.

14. A reduced coenzyme Q-10 (CoQ-10) composition, consisting essentiallyof:

a sufficient amount of dihydrolipoic acid (DHLA) to reduce CoQ-10 to areduced form of CoQ-10 in greater than 95% by weight.

15. The composition of paragraph 14, wherein the composition does notinclude an ethanolic solution containing 8% water.

16. The composition of either paragraphs 14 or 15, further comprising acarrier.

17. The composition of paragraph 16, wherein the carrier is DHLA.

18. The composition of paragraph 16, wherein the carrier is a vegetableoil, a fish oil or a combination thereof.

19. The composition of any of paragraphs 14 through 18, furthercomprising a an antioxidant or an antioxidant enzyme.

20. The composition of paragraph 19, wherein the antioxidant is vitaminE, a vitamin E derivative, vitamin C, a vitamin C derivative, probucol,lycopene, vitamin A, a carotenoid, vitamin B, vitamin B1, a vitamin Bderivative, a flavonoid, a polyphenol, glutathione, pyrroloquinolinequinone, Pycnogenol, Flavangenol, selenium, a lipoic acid, a lipoic acidderivative, a carnitine (e.g., L-carnitine) or mixtures thereof.

21. The composition of paragraph 19, wherein the antioxidant enzyme issuperoxide dismutase, glutathione peroxidase, glutathione-S-transferase,glutathione reductase, catalase and ascorbic acid peroxidase or mixturesthereof.

22. The composition of any of paragraphs 14 through 21,

wherein the pH range of the composition is between about a pH of 6 and apH of 3.

23. The composition of paragraph 22, wherein the pH range is betweenabout 5.5 and about 3.5.

24. The composition of paragraph 23, wherein the pH range is betweenabout 4 and about 3.5.

25. The composition of paragraph 24, wherein the pH range is betweenabout 3.9 to about 3.8.

26. The composition of any of paragraphs 14 through 25, wherein thereduced form of CoQ-10 is present in an amount of about 98.5% by weightor greater.

27. The composition of any of paragraphs 14 through 25, whereinessentially all of the CoQ-10 is present in the reduced form.

28. A soft gelatin capsule that encapsulates a reduced coenzyme Q-10(CoQ-10) composition, comprising:

a reduced coenzyme Q-10 (CoQ-10) composition, comprising:

a sufficient amount of dihydrolipoic acid (DHLA) to reduce CoQ-10 to areduced form of CoQ-10 in greater than 95% by weight; and

a soft gelatin capsule that encapsulates the reduced coenzyme Q-10(CoQ-10) composition.

29. The soft gelatin capsule of paragraph 16, wherein, the reducedCoQ-10 composition does not include an ethanolic solution that contains8% water.

30. The soft gelatin capsule of either paragraphs 28 or 29, furthercomprising a carrier.

31. The soft gelatin capsule of paragraph 30, wherein the carrier isDHLA.

32. The soft gelatin capsule of paragraph 30, wherein the carrier is avegetable oil, a fish oil or a combination thereof.

33. The soft gelatin capsule of any of paragraphs 28 through 32, furthercomprising a an antioxidant or an antioxidant enzyme.

34. The soft gelatin capsule of paragraph 33, wherein the antioxidant isvitamin E, a vitamin E derivative, vitamin C, a vitamin C derivative,probucol, lycopene, vitamin A, a carotenoid, vitamin B, vitamin B1, avitamin B derivative, a flavonoid, a polyphenol, glutathione,pyrroloquinoline quinone, Pycnogenol, Flavangenol, selenium, a lipoicacid, a lipoic acid derivative, a carnitine (e.g., L-carnitine) ormixtures thereof.

35. The soft gelatin capsule of paragraph 33, wherein the antioxidantenzyme is superoxide dismutase, glutathione peroxidase,glutathione-S-transferase, glutathione reductase, catalase and ascorbicacid peroxidase or mixtures thereof.

36. The soft gelatin capsule of any of paragraphs 28 through 35, whereinthe pH range of the composition is between about a pH of 6 and a pH of3.

37. The soft gelatin capsule of paragraph 36, wherein the pH range isbetween about 5.5 and about 3.5.

38. The soft gelatin capsule of paragraph 37, wherein the pH range isbetween about 4 and about 3.5.

39. The soft gelatin capsule of paragraph 38, wherein the pH range isbetween about 3.9 to about 3.8.

40. The soft gelatin capsule of any of paragraphs 28 through 39, whereinthe reduced form of CoQ-10 is present in an amount of about 98.5% byweight or greater.

41. The soft gelatin capsule of any of paragraphs 28 through 39, whereinessentially all of the CoQ-10 is present in the reduced form.

42. A soft gelatin capsule that encapsulates a reduced coenzyme Q-10(CoQ-10) composition, consisting essentially of:

a sufficient amount of dihydrolipoic acid (DHLA) to reduce CoQ-10 to areduced form of CoQ-10 in greater than 95% by weight; and

a soft gelatin capsule that encapsulates the reduced coenzyme Q-10(CoQ-10) composition.

43. The soft gelatin capsule of paragraph 42, wherein the soft gelatincapsule does not include an ethanolic solution containing 8% water.

44. The soft gelatin capsule of either paragraphs 42 or 43, furthercomprising a carrier.

45. The soft gelatin capsule of paragraph 44, wherein the carrier isDHLA.

46. The soft gelatin capsule of paragraph 44, wherein the carrier is avegetable oil, a fish oil or a combination thereof.

47. The soft gelatin capsule of any of paragraphs 42 through 46, furthercomprising a an antioxidant or an antioxidant enzyme.

48. The soft gelatin capsule of paragraph 47, wherein the antioxidant isvitamin E, a vitamin E derivative, vitamin C, a vitamin C derivative,probucol, lycopene, vitamin A, a carotenoid, vitamin B, vitamin B1, avitamin B derivative, a flavonoid, a polyphenol, glutathione,pyrroloquinoline quinone, Pycnogenol, Flavangenol, selenium, a lipoicacid, a lipoic acid derivative, a carnitine (e.g., L-carnitine) ormixtures thereof.

49. The soft gelatin capsule of paragraph 47, wherein the antioxidantenzyme is superoxide dismutase, glutathione peroxidase,glutathione-S-transferase, glutathione reductase, catalase and ascorbicacid peroxidase or mixtures thereof.

50. The soft gelatin capsule of any of paragraphs 42 through 49, whereinthe pH range of The soft gelatin capsule is between about a pH of 6 anda pH of 3.

51. The soft gelatin capsule of paragraph 50, wherein the pH range isbetween about 5.5 and about 3.5.

52. The soft gelatin capsule of paragraph 51, wherein the pH range isbetween about 4 and about 3.5.

53. The soft gelatin capsule of paragraph 52, wherein the pH range isbetween about 3.9 to about 3.8.

54. The soft gelatin capsule of any of paragraphs 42 through 53, whereinthe reduced form of CoQ-10 is present in an amount of about 98.5% byweight or greater.

55. The soft gelatin capsule of any of paragraphs 42 through 53, whereinessentially all of the CoQ-10 is present in the reduced form.

56. A process to prepare a reduced coenzyme Q-10 solution, comprisingthe step of:

contacting coenzyme Q-10 (CoQ-10) with a sufficient amount ofdihydrolipoic acid (DHLA) to reduce the CoQ-10 to a reduced form ofCoQ-10 in greater than about 95% by weight.

57. The process of paragraph 56, wherein excess DHLA is used, such thatthe DHLA is also a carrier.

58. The process of either paragraph 56 or 57, wherein the process isconducted at a pH of below about a pH of 6.

59. The process of either paragraph 56 or 57, wherein the process isconducted at a pH of below about a pH of 5.

60. A method to treat periodontal diseases, mitochondrial relateddiseases and disorders, Parkinson's disease, Prater-Willey syndrome,migraine headaches or headaches comprising the step of administering tothe individual in need thereof, an effective amount of any of thecompositions of paragraphs 1 through 55.

61. A method to prepare reduced coenzyme Q-10 comprising the step ofcontacting a molar excess of dihydrolipoic acid with a mole of coenzymeQ-10, wherein the composition does not include an ethanolic solutioncontaining 8% water.

62. The composition of paragraph 2, wherein the carrier is a monocyclicterpene.

63. The composition of paragraph 62, wherein the monocyclic terpeneincludes limonene, ginger oil, lavandin oil, peppermint oil, camphoroil, geranium oil, orange oil, lemon oil, lavender oil, tea tree oil,rosemary oil or mixtures thereof.

In a particular embodiment, the antioxidants are a mixture of one ormore of L-carnitine, glutathione and VB1

The following examples are intended to be illustrative only and shouldnot be considered limiting.

Example 1 Dissolution and Reduction of CoQ10 by DHLA (Preparation of 13%Solution)

1.1 g (1.27 mmol) CoQ10 (in its oxidised form) were added to 7.1 g (34.1mmol) DHLA. The mixture was stirred until a uniform solution wasachieved. The solution was kept at 25° C. for 1 week, afterwards HPLCanalysis (UV detector at 210 nm) was performed. The ratio of oxide formof CoQ10 (ubiquinone) and reduced form (ubiquinol form) of CoQ10 in themixture was 1:5 to 98.5. The pH-value of the solution was about 3.80(measured by Metrohm 827 pH Lab).

Example 2 Protection of Reduced Coenzyme Q10 Against Re-Oxidation UnderStorage Conditions

3 g (3.48 mmol) CoQ10 (oxidized form) were dissolved in 40 ml THF, and0.32 g (8.65 mmol) NaBH₄ were added. The solution was kept at 30° C. for1 hour. Under HPLC analysis (UV detector at 210 nm), the oxidized formof CoQ10 (ubiquinone) was not detected in the solution.

Afterwards 30 ml CH₂Cl₂ were added, and the organic layer was washedthree times with 6 mol/L HCl, dried with anhydrous Na₂SO₄, and 8.1 g(38.9 mmol) DHLA were added. The solution was distilled under vacuum toremove the CH₂Cl₂ and THF. The residue solution was stored for 1 week.Under HPLC analysis (UV detector at 210 nm), it was found that nore-oxidation of the reduced CoQ10 occurred.

Example 3 Dissolution Of CoQ10 in DHLA; Temperature Dependence of theSolubility

Coenzyme Q10 was dissolved in DHLA at various temperatures. FIG. 1exhibits the solubility of CoQ10 at various temperatures. The ordinateshows the percentage of dissolved CoQ10 in DHLA.

When a solution of reduced CoQ10 in DHLA is cooled, the reduced CoQ10will sometimes precipitate. Upon re-heating the reduced form, CoQ10 isre-dissolved in DHLA. After repeating this cycle, the oxidised form ofCoQ10 could not be detected.

HPLC analysis, furthermore, shows that a redox reaction takes place inthe CoQ10-DHLA solution. In this regard, the amount of DHLA that isoxidized is equal to the amount of CoQ10 that is reduced.

Example 4 Preparation of an 8% Solution of CoQ10 in DHLA

0.9 g (1.04 mmol) CoQ10 (oxidized form) were added to 11.09 g (53.3mmol) DHLA, The mixture was stirred until a uniform solution wasachieved. The solution was kept at 25° C. for 1 week, afterwards HPLCanalysis (UV detector at 210 nm) was performed. The ratio of oxide formof CoQ10 and reduced form (ubiquinol form) of CoQ10 in the mixture is1:5 to 98.5. The pH-value of the solution was about 3.80 to 3.90.

The solution was kept at room temperature for about 1 month with nochange in the composition detected as determined by HPLC.

Example 5 Analysis of the Transformation of DHLA to Lipoic Acid (LA) andStability of Reduced Form of CoQ10 by HPLC

Analytical Methods

Instruments and Material:

HPLC: Waters 600 pump with 717plus autosampler and 2996 PDA detector

Balance: Sartorius BP 211D

Regents: Acetonitrile (HPLC grade, Fisher), Distilled water (Nestle),Methanol (Fisher, HPLC grade)

Standards: DHLA (89.3%), LA from Sigma, 99.0%, oxidized CoQ10 (98.5%)

HPLC Conditions

LA and DHLA:

Mobile phase: 0.03% H3PO4: Acetonitrile=60:40

Column: Agilent ellipse XDB-C18 (150 mm*4.6 mm, 5 μm)

Temperature: 30° C.

UV-detection: 220 nm

Injection volume: 10 μl

Flow rate: 1.0 ml/min

Reduced and oxidized CoQ10:

Mobile phase: Methanol: Ethanol=75:25

Column: Waters Symmetry C18 (150 mm*4.6 mm, 5μm)

Temperature: 30° C.

UV-detection: 210 nm

Injection volume: 2 μl

Flow rate: 1.0 ml/min

The samples were made by dissolving 50-100 mg CoQ10-DHLA solution in a 5ml volumetric bottle with methanol/ethanol (50/50, v/v).

The results are listed in Table 1.

TABLE 1 The area % of LA and reduced CoQ10 vs. reaction time Area %Time(hour) LA Reduced CoQ10 0.5 2.03 4.57 2.5 2.37 6.5 3.39 21.53 216.91 23 7.14 69.03 25 7.33 73.46 28 7.76 85.77 30 7.92 87.18 34 8.2 498.51 94.43 52 8.63 96.82 56 8.12 97.24 70 7.36 97.44

Table 1 provides the respective area-% of the lipoic acid (LA) (ascompared to DHLA) and of the reduced form of CoQ10 (as compared to theoxidized form of CoQ10) in the CoQ10-DHLA solution.

The results show that after about 52 hours, the oxidized CoQ10 wasalmost completely reduced by DHLA. At the first 40 hours the content ofreduced CoQ10 increases very fast, then the reaction rate slows down.

When close to the end point of the reaction, the reduced CoQ10 is verysensitive to the air and can be easily re-oxidized, so the content ofreduced CoQ10 remains at about 9798%.

Example 6

20 g CoQ10 (oxidized form) were added to 80 g DHLA. The mixture wasslowly stirred and heated at 37° C., until the solid was fullydissolved. The reaction time until CoQ10 was totally dissolved wasaround 7 days. After sealing the container with the CoQ10/DHLA solution,the reduced form of CoQ10 remained stable for at least one month(reduced CoQ10 value of 97-98% or more via HPLC as described herein).The pH-value of the solution was about 3.80 to 3.90.

Example 7

10 g CoQ10 (oxidized form) were added to 5 g DHLA. The mixture wasstirred and heated to 50° C. until the solid was fully dissolved. Thebottle containing the solution was sealed and kept at a temperature of50° C. for 70 days. Afterwards, the ratio of the reduced form of CoQ10(ubiquinol) and the oxide form of CoQ10 in the solution was found to beover 99:1 as determined by HPLC described herein. The pH-value of thesolution was about 3.80 to 3.90.

Example 8

1.1 g CoQ-10 was dissolved in 7.1 g DHLA at 25° C. The formation of aCoQ-10 radical was followed by UV spectrophotometrically. If thereaction would proceed via radicals, it is expected that the CoQ-10radical would appear as a prominent band around 480 nm.

However, there was no indication of radical formation as evidenced bythe lack of a band at 480 nm. (See FIG. 2) This suggests that thereduction of the CoQ-10 occurs via a 2-electron transfer reactionmechanism. This would appear logical as at the pH of the reaction(3.80-3.90) DHLA is not susceptible to radical formation, which would bea prerequisite for a radical reaction.

In FIG. 2, the band at approximately 320 nm indicates generation oflipoic acid (max. 320 nm) and a band at approximately 480 nm would bethe region where a semiubiquinone radical would occur.

FIG. 2 was generated 1-hour post initiation of the reaction: As seen,lipoic acid is formed, but there is no indication of a ubiquinoneradical.

FIG. 3 was taken 6 hours post initiation. FIG. 3 demonstrates that thereis no indication of a ubiquinone radical.

FIGS. 2 and 3 provide evidence that a 2-electron transfer reductionoccurs between the components without radical formation.

Example 9

The following example shows the time course of the reduction reactionbetween CoQ-10 and DHLA. As seen in FIG. 4, there is a linearrelationship within the first 30 hours of reaction time, indicating thatin a 8.9% CoQ10 solution (91.1% DHLA w/w, pH=about 3.8 to about 3.9,ambient temperatures), about 0.3 mmol reduced CoQ10/100 g solution areformed/hour.

The linear relationship noted in FIG. 4, also provides evidence for anon-radical reduction of CoQ-10.

What is interesting is that about 3 times more DHLA is oxidized (about30 mmol) than are required for reduction of CoQ-10 (See Table 2). Themost likely explanation is that equilibrium between DHLA/LA is reachedon the basis of pK-values.

TABLE 2 mmol reduced CoQ10 Reaction Time mmol LA formed formed 0.5 9.00.47 2.5 10.5 — 6.5 15.0 2.22 21 30.6 — 23 31.6 7.12 25 32.4 7.58 2834.3 8.85 30 35.0 8.99 34 36.3 — 49 37.6 9.74 52 38.2 9.98 56 35.910.03  70 32.5 10.05 

Bioavailablity Testing

Material and Treatment:

Five male Sprague-Dawley rats (weighing 220-250 g, 7-8 weeks of age) canbe used used in each treatment group. Treatment groups would includethree groups. Group A would be with coenzyme Q10 with DHLA; Group B iswith coenzyme Q10 with ascorbyl palmitate; and Group C would be withonly coenzyme Q10. Rats would be dosed orally with coenzyme Q10 samplesand the coenzyme Q10 dosage would be 20 mg/Kg.

The coenzyme Q10 with DHLA would be from the example 6 (Q10/DHLA=¼,w/w);

The coenzyme Q10 plus ascorbyl palmitate, would be prepared withcoenzyme Q10/ascorbyl palmitate=¼, w/w, emulsified with a suitableemulsifying agent, such as a Tween;

Coenzyme Q10 would the reduced form of coenzyme Q10 without otherfunctional agents.

Method and Detection:

Blood sampling (0.5 mL) would be taken after dosing (t=0) and 10, 20,30, 40, 50, 60, 90, 120, 150, 180, 240 minutes after dosing.

An HPLC assay, measuring at 210 nm, would be used to detect for thequantity of reduced coenzyme Q10 in blood samples.

Analysis Method:

The mean reduced coenzyme Q10 plasma concentration of samples versustime after a single oral dose would be compared.

Expected Results:

The results should be that the reduced coenzyme Q10 plasma concentrationof Group A is several times higher than that of Group B, and thecoenzyme Q10 plasma concentration of Group C would be very low.

CONCLUSION

Data obtained from the rats given oral administration of coenzyme Q10can reveal coenzyme Q10 with DHLA was best absorbed with the bestprotection of reduced Q10 as well as the best retention of reducedcoenzyme Q10 in vivo.

These results would account or the better bioavailability of theDHLA/reduced coenzyme Q10 product of the present invention.

Although the present invention has been described with reference topreferred embodiments, persons skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention. All references cited throughout thespecification, including those in the background, are incorporatedherein in their entirety. Those skilled in the art will recognize, or beable to ascertain, using no more than routine experimentation, manyequivalents to specific embodiments of the invention describedspecifically herein. Such equivalents are intended to be encompassed inthe scope of the following claims.

1. A ubiquinol composition consisting of from about 0.1% by weight toabout 50% by weight of ubiquinol dissolved in dihydrolipoic acid.
 2. Theubiquinol composition of claim 1, wherein the composition isencapsulated within a soft gelatin capsule.
 3. A method to treatperiodontal diseases, mitochondrial related diseases and disorders,Parkinson's disease, Prater-Willey syndrome, migraine headaches orheadaches comprising the step of administering to the individual in needthereof, an effective amount of the ubiquinill composition of claim 1.